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Hiroshi Suzuki

Publications and source records attributed to Hiroshi Suzuki.

At least 19 recordsLinked to original sources
PubMed2025

Mitochondrial dysfunction in MED13 variant-associated disease: a case of infantile spasms, cardiomyopathy and hepatomegaly.

Here we report a de novo heterozygous MED13 variant (c.2503C>T, p.Pro835Ser) in an infant presenting with infantile spasms, hypertrophic cardiomyopathy and hepatomegaly. Autopsy revealed mitochondrial abnormalities in cardiac and hepatic tissues, with reduced respiratory chain complex activity. This is the first case report linking a MED13 variant to systemic mitochondrial dysfunction, suggesting a novel pathogenic mechanism.

Journal Article↗
PubMed2005

Exposure of C57BL/6J male mice to an electric field improves copulation rates with superovulated females.

It is well-known that there are considerable strain differences in the relative copulation rates between male and superovulated female mice. In particular, the C57BL/6J strain of mice has a lower rate of successful copulation. We examined the effect of exposure to an electric field on sexual behavior in C57BL/6J male mice. When C57BL/6J males were exposed to a 50 Hz, 45 kV/m electric field for 30 min per day for 11 days and placed in a cage with a superovulated female of the same strain, the successful copulation rates of males was significantly improved compared with unexposed males (P<0.05). These results suggest that the exposure of C57BL/6J male mice to an electric field improves their sub-fertility activity in mating with superovulated females.

Animals↗
PubMed2005

Importance of adequate immunosuppressive therapy for the recovery of patients with "life-threatening" severe exacerbation of chronic hepatitis B.

AIM: Hepatitis B virus (HBV) re-activation often occurs spontaneously or after withdrawal of immunosuppressive therapy in patients with chronic hepatitis B. Severe exacerbation, sometimes developing into fulminant hepatic failure, is at high risk of mortality. The efficacy of corticosteroid therapy in "clinically severe" exacerbation of chronic hepatitis B has not been well demonstrated. In this study we evaluated the efficacy of early introduction of high-dose corticosteroid therapy in patients with life-threatening severe exacerbation of chronic hepatitis B. METHODS: Twenty-two patients, 14 men and 8 women, were defined as "severe" exacerbation of chronic hepatitis B using uniform criteria and enrolled in this study. Eleven patients were treated with corticosteroids at 60 mg or more daily with or without anti-viral drugs within 10 d after the diagnosis of severe disease ("early high-dose" group) and 11 patients were either treated more than 10 d or untreated with corticosteroids ("non-early high-dose" group). RESULTS: Mean age, male-to-female ratio, mean prothrombin time (PT) activity, alanine transaminase (ALT) level, total bilirubin level, positivity of HBeAg, mean IgM-HBc titer, and mean HBV DNA polymerase activity did not differ between the two groups. Ten of 11 patients of the "early high-dose" group survived, while only 2 of 11 patients of the "non-early high-dose" group survived (P<0.001). During the first 2 wk after the introduction of corticosteroids, improvements in PT activities and total bilirubin levels were observed in the "early high-dose" group. Both ALT levels and HBV DNA polymerase levels fell in both groups. CONCLUSION: The introduction of high-dose corticosteroid can reverse deterioration in patients with "clinically life-threatening" severe exacerbation of chronic hepatitis B, when used in the early stage of illness.

Acute Disease↗
PubMed2005

Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent.

Accumulated evidence suggests that Parp-1 is involved in DNA repair processes, including base excision repair, single-strand and double-strand break repairs. To understand the precise role of Parp-1 in genomic stability in vivo, we carried out mutation analysis using Parp-1 knockout (Parp-1-/-) mice harboring two marker genes, gpt and red/gam genes. Spontaneous mutant frequencies of both genes in the bone marrows and livers did not differ significantly between Parp-1-/- and Parp-1+/+ mice (P>0.05). After treatment with an alkylating agent, N-nitrosobis(2-hydroxypropyl)amine (BHP), the mutant frequency of the red/gam genes in the liver in Parp-1-/- mice was 1.6-fold higher than that in Parp-1+/+ mice (P<0.05). Categorization of the mutations revealed that deletions larger than 1 kb or those accompanying 1-5 bp insertions at the deletion junctions, as well as rearrangements, were more frequently observed in Parp-1-/- than in Parp-1+/+ mice (P<0.05, respectively). In contrast, mutant frequencies of the gpt gene in the livers of Parp-1(-/-) and Parp-1(+/+) mice after BHP treatment were both elevated and there was no significant difference between the genotypes. These results indicate that Parp-1 is implicated in suppressing deletion mutations in vivo, especially those accompanying small insertions or rearrangements.

Alkylating Agents↗
PubMed2005

Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.

In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.

Cell Line↗
PubMed2005

Effect of maternal autoantibodies on fetal cardiac conduction: an experimental murine model.

The pathogenesis of congenital heart block (CHB) remains unclear. The occurrence rate of neonatal CHB is low, even in murine models of lupus erythematosus. The assessment of heart block in murine maternal lupus models by measuring atrioventricular conduction in neonatal offspring is potentially confounded by fetal wastage. We therefore sought to develop a murine CHB model with a superior immune response and to use embryonic Doppler echocardiography to observe conduction system damage in the fetus. Mature 8-wk-old female C3H/HeJ mice (n=43) were immunized with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens. ELISA confirmed that significant serum autoantibodies developed in all three immunized groups when compared with controls. Starting at 13 d of gestation, a significantly lower fetal heart rate (HR) and a higher percentage of fetal bradycardia/atrioventricular block (AVB, nonadvanced second degree) were observed in all immunized groups, compared with controls. There was 9-18% nonadvanced second-degree AVB in immunized groups and 0% in controls at <18 d of gestation. Neonatal electrocardiograms demonstrated only 1 degrees AVB in immunized groups. Maternal immunization with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens resulted in AVB in a significant percentage of fetuses, however, lesser degrees of AVB were seen at birth. Significant fetal bradycardia and AVB may be missed by assessment only at birth in murine models of CHB due to fetal wastage.

Animals↗
PubMed2005

Clearance of apoptotic cells is not impaired in mouse embryos deficient in class A scavenger receptor types I and II (CD204).

Elimination of apoptotic cells is an important mechanism to maintain proper embryonal morphogenesis. The class A scavenger receptor type I, II (CD204), one of the major receptors expressed on macrophages, is a receptor actively involved in recognition and ingestion of apoptotic cells. To clarify the role of CD204 in embryonic morphogenesis, we performed immunohistochemical and immunoelectron microscopic studies using CD204-deficient mouse embryos. In control mice, almost all macrophages expressed CD204 from embryonic day 9.5 (E9.5). Phagocytes engulfing dead cells in the E13.5 interdigit region showed strong expression of CD204, indicating that CD204 was actively involved in apoptotic cell clearance. However, CD204 is not essential for the embryonic clearance of apoptotic cells, because CD204-deficient embryos developed normally without any retardation in footplate remodeling. Up-regulation of CD36 in CD204-deficient fetal macrophages suggested that CD36 substitutes for CD204 function. We also found that mesenchymal cells frequently engulfed apoptotic cells especially in early embryonal stages. These data suggest that CD204 is partially but not essentially involved in apoptotic cell clearance in embryogenesis. During early embryonal development, mesenchymal cells, rather than macrophages, play a major role in apoptotic cell clearance.

Animals↗
PubMed2005

YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action.

We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC(50)) value for YM-53403. The value, 0.20 microM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents.

Animals↗
PubMed2005

Impact of daily high-dose IFNalpha-2b plus ribavirin combination therapy on reduction of ALT levels in patients with chronic hepatitis C with genotype 1 and high HCV RNA levels.

The possibility of delaying progression to hepatocellular carcinoma in chronic hepatitis C patients with genotype 1 and high viral titers with baseline ALT levels of >/=50IU/L was examined by administration of IFN plus ribavirin combination therapy using ALT normalization as index and IFN monotherapy as control. The rate of sustained ALT normalization (ALT normal at 24 weeks after the end of treatment) was 28.1% with combination therapy and 10.5% with IFN monotherapy (P=0.001). Furthermore, the number of patients with sustained viral response (SVR) and with sustained ALT normalization in non-SVR patients was also significantly higher in the combination therapy versus monotherapy group. Mean ALT values during treatment and for 6 months after the end of treatment were significantly lower with combination therapy versus monotherapy even in virological nonresponders, as well as significantly lower during the post-treatment observation period in patients who relapsed after the end of treatment. Since increase in the rate of sustained ALT normalization and SVR were successfully achieved, inhibition of progression to hepatocellular carcinoma should be studied with long-term IFN and ribavirin combination therapy.

Journal Article↗
PubMed2005

Peak rotavirus activity shifted from winter to early spring in Japan.

BACKGROUND: Since 1910, there have been many studies on acute gastroenteritis in children in Japan. These diseases, namely Kasei-shoni-kolera (pseudocholera infantum) or banshu-otosho (late autumn vomiting disease), are historically known to occur in the cooler season with a peak in November or December. Earlier we confirmed their causation by rotaviruses but found peaks in January or February from 1974 to 1981. The aim of the present study was to confirm the temporal shift in peak rotavirus activity. METHODS: Under the National Epidemiological Surveillance of Infectious Diseases program from 1983 through 2003, rotavirus positive patients 0-3 years old and clinically diagnosed with "infantile vomiting and diarrhea" at sentinel clinics were examined. Fecal samples were screened by electron microscopy and/or using commercial latex agglutination kits at prefectural/municipal Public Health Institutes, and we determined the trend for the "peak" month during 21 seasons. RESULTS: Peak rotavirus activity shifted gradually from January to March during the 21 consecutive seasons. The mean duration from December to the peak month (mean beginning peak duration) of the rotavirus season significantly varied among 3 periods of 7 consecutive seasons (1.7 +/- 0.5 months in 1982/1983-1988/1989, 2.3+/-0.8 months in 1989/1980-1995/1996, and 3.1 +/- 0.7 months in 1996/1997-2002/2003, respectively; P = 0.0026 by 1-way analysis of variance). This time series shift in the peak rotavirus infection was statistically significant (P = 0.0003 for trend). CONCLUSION: Our findings confirmed that the temporal trend in peak rotavirus activity in Japan has shifted gradually from winter to early spring for unknown reasons.

Age Distribution↗
PubMed2005

Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury.

Bach1 is a transcriptional repressor of the cytoprotective enzyme heme oxygenase-1 (HO-1). Although HO-1 protects against atherosclerosis, the function of Bach1 in this process is poorly understood. We isolated peritoneal macrophages and aortic smooth muscle cells (SMC) from wild-type and bach1-deficient mice. bach1-Deficient macrophages expressed increased levels of HO-1 and showed elevated phagocytic activity when incubated with 0.75 microm microspheres. In SMC, bach1-ablation resulted in increased expression of HO-1 and decreased proliferation in bromodeoxyuridine incorporation assay as compared with wild-type cells. The up-regulated phagocytic activity and reduced SMC proliferation of bach1-deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1. In wild-type mice, cuff placement around femoral artery caused pronounced intimal proliferation without affecting the media, thus resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1-deficient mice had less degree of intimal growth (I/M ratio of 45.6%). These results indicate that Bach1 plays a critical role in the regulation of HO-1 expression, macrophage function, SMC proliferation and neointimal formation. Bach1 may regulate gene expression in these cells during inflammation and atherogenesis.

Animals↗
PubMed2005

Molecular epidemiology of respiratory syncytial virus infections among children with acute respiratory symptoms in a community over three seasons.

To study the molecular epidemiology of respiratory syncytial virus (RSV) in a community, children with acute respiratory symptoms at a pediatric outpatient clinic in Niigata, Japan, were analyzed over three seasons from November 2001 to July 2004. Of 499 nasopharyngeal aspirate specimens, 185 (37.1%) were RSV positive, and only 8 (4.5%) of 177 patients were shown by the reverse transcription (RT)-PCR method to be reinfected. RSV infection occurred beginning in the early winter, and the rates declined in the spring. The predominant subgroup changed from A to B and returned to A over the three seasons. Phylogenetic analysis also revealed that multiple genotypes cocirculated each year, with genotype GA5 of subgroup A predominating in the 2001-2002 and the 2003-2004 seasons. A new genotype of subgroup B (named BA, according to the nomenclature for viruses) with a 60-nucleotide insertion in the second variable region of the attachment glycoportein protein was predominant as an emerging strain in the 2002-2003 season, but this was not associated with new epidemiological or clinical features, unlike the cases of disease caused by other genotypes in the other seasons. In conclusion, our molecular analysis of RSV confirms that multiple genotypes cocirculate each year and that the genotype predominating may shift with the season. Support for determination of the genotype by RT-PCR as an effective tool for characterization of RSV circulation patterns in the community is provided.

Acute Disease↗
PubMed2005

The impact of high-density barium use in double contrast radiographic methods for gastric cancer screening in Niigata, Japan.

Use of high-density barium (= or > 180 w/v%) has been widely spread in community-based mass screening for gastric cancer in Japan. However, the impact on outcomes of the screening has not been fully evaluated. Then, we investigated the advantage of high-density barium use by comparing the outcomes between a period with high-density barium and that with low-density barium (< 180 w/v%) each for 3 consecutive years between 1991 and 2002 at 5 medical examination organizations in Niigata Prefecture, Japan. Multivariate logistic regression analysis adjusted for age, sex and medical organization revealed that the introduction of high-density barium decreases the positive finding rate in initial mass screening x-ray examinations by 12% (odds ratio, 0.88; 95% confidence interval, 0.86 - 0.90) and increase the gastric cancer detection rate by diagnostic examination by 15% (odds ratio, 1.15; 95% confidence interval, 1.01-1.31). We conclude that introduction of high-density barium has improved the efficiency of mass screening for gastric cancer by decreasing unnecessary diagnostic examinations and reducing the total personal and public health costs. Thus, nationwide use of high-density barium is recommended for mass gastric cancer screening in Japan.

Adult↗
PubMed2004

Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen.

The purpose of this study is to examine the significance of efflux transporters in the small intestine to extrude glucuronide (G) and sulfate (S) conjugates into the intestinal lumen. From this standpoint, we performed in situ intestinal perfusion experiments by using Eisai hyperbilirubinemic rats (EHBRs) in which the multidrug resistance protein 2 (Mrp2/Abcc2) is hereditarily defective and breast cancer resistance protein (Bcrp1/Abcg2) knockout mice. The intestinal lumen of EHBRs and Bcrp1 (-/-) mice was perfused with medium containing 4-methylumbelliferone (4MU) and E3040 [6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridilmethyl) benzothiazole] to determine the efflux of metabolites into the outflow. The efflux of E3040-glucuronide (G) in EHBRs was significantly lower compared with that in normal rats. However, no significant difference was observed for the efflux of 4MU-G, 4MU-sulfate (S), and E3040-S between EHBRs and normal rats. In contrast, the efflux of intracellularly formed 4MU-G, 4MU-S, and E3040-G in Bcrp1 (-/-) mice was significantly lower than that in normal mice. Therefore, Bcrp1 has an important role in extruding glucuronide and sulfate conjugates formed in enterocytes into the intestinal lumen, whereas Mrp2 is responsible for the efflux of some glucuronide conjugates.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

In vivo imaging of C. elegans ASH neurons: cellular response and adaptation to chemical repellents.

ASH sensory neurons are required in Caenorhabditis elegans for a wide range of avoidance behaviors in response to chemical repellents, high osmotic solutions and nose touch. The ASH neurons are therefore hypothesized to be polymodal nociceptive neurons. To understand the nature of polymodal sensory response and adaptation at the cellular level, we expressed the calcium indicator protein cameleon in ASH and analyzed intracellular Ca(2+) responses following stimulation with chemical repellents, osmotic shock and nose touch. We found that a variety of noxious stimuli evoked strong responses in ASH including quinine, denatonium, detergents, heavy metals, both hyper- and hypo-osmotic shock and nose touch. We observed that repeated chemical stimulation led to a reversible reduction in the magnitude of the sensory response, indicating that adaptation occurs within the ASH sensory neuron. A key component of ASH adaptation is GPC-1, a G-protein gamma-subunit expressed specifically in chemosensory neurons. We hypothesize that G-protein gamma-subunit heterogeneity provides a mechanism for repellent-specific adaptation, which could facilitate discrimination of a variety of repellents by these polymodal sensory neurons.

Adaptation, Biological↗
PubMed2004

Studies of nonnucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Design and synthesis of thiazolidenebenzenesulfonamides.

A random high-throughput screening (HTS) program to discover novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out with MT-4 cells against a nevirapine-resistant virus, HIV-1(IIIB-R). The primary hit, a thiazolidenebenzenesulfonamide derivative, possessed good activity. A systematic modification program examining various substituents at the 3-, 4-, and 5-positions on the thiazole ring afforded compounds with enhanced anti-HIV-1 and reverse transcriptase (RT) inhibitory activities. These results confirm the important role of the substituents at these positions and the thiazolidenebenzenesulfonamide motif as a valuable lead series for the next generation NNRTIs.

Benzenesulfonates↗
PubMed2004

One-pot synthesis of helical aromatics: stereoselectivity, stability against racemization, and assignment of absolute configuration assisted by experimental and theoretical circular dichroism.

Helical aromatics (1) were synthesized via one step in good quantity by solvent-free condensation of N,N'-p-phenylenediamine (2) and various carboxylic acids in the presence of a Lewis acid. Microwave irradiation greatly facilitated the condensation reaction to furnish 1 with a 100% diastereo- and a 50% enantioselectivity, when a chiral carboxylic acid was utilized. 1f, derived from 2-methylglutaric acid, was quite stable, no racemization taking place even at 200 degrees C. The assignment of the absolute configurations to the helical aromatics has been achieved by experimental and theoretical CD spectra calculated by time-dependent density functional theory.

Journal Article↗